Porphyromonas gingivalis, a host-adapted Gram (-) anaerobe and a major periodontal pathogen in the oral cavity, can also successfully colonize in the oral mucosa. Epithelial cells are emerged as major arm of initial defenses in mucosal surfaces. However, the rising multi-disciplinary evidence critically underpins that gingival epithelial cells (GECs) can be usurped as privileged growth niches and a reservoir by P. gingivalis, which can intracellularly multiply and remain unscathed in GECs. Despite the P. gingivalis infection in the epithelial cells is extensively studied, the pathogen?s intracellular life in this important cell type has been poorly studied. Our lab recently revealed that formation of autophagosomes is very critical for the P. gingivalis? intracellular replication and evasion of the anti-microbial degradation pathways in the primary GECs. Our novel preliminary findings also support that lipidation of LC3-C, a key molecule in the ?selective autophagy? pathway, which targets intracellular pathogens is significantly modulated by P. gingivalis under the control of an anti- stress molecule, HSP27. Further, glutathione peroxidase (GpX1), a major host redox balance enzyme and a regulator of autophagic flux largely impacted on the global LC3 lipidation state of GECs upon infection. The inhibition of either HSP27 or GpX1 appears to severely affect the intracellular trafficking and viability of the microorganism. Our overarching hypothesis is that P. gingivalis induces a distinct form of selective (pro- bacterial) autophagy, which results in protecting of bacterial life and ultimately securing of P. gingivalis? persistence in the oral mucosa. To test our novel hypothesis, we will pursue two-pronged approach, where we propose the selective autophagy requires tightly coordinated actions of HSP27 and GpX1 to form autophagosomes that fully function as protected replicative niches for P. gingivalis? survival in GECs. Aim 1 will define the selective molecular machinery that drives P. gingivalis-containing autophagosome assembly under the control of HSP27 and the mechanisms that disrupt autophagic flux for the evasion of cellular degradation pathways. Aim 2 will establish the role of GpX1 in regulating the selective autophagy in infection by contributing to redox homeostasis and suppressing autophagolysosomal machinery. Both aims will employ reductionist primary GECs culture systems to functionally dissect out the mechanisms and phenotypically characterize the molecular events and sub-cellular components. Aim 3 will establish the dual significance of these two components using oral epithelial-tissue-specific knockout mice models. Thus, this proposal aims to fill a significant gap in our fundamental knowledge that is how P. gingivalis, a facultatively intracellular pathogen, establishes a privileged niche in the unhospitable GEC environment and converts nutritionally rich epithelial cells into potentially a central reservoir for successful bacterial growth and persistence in the oral mucosa. Ultimately, the knowledge gained may translate into molecular strategies that can control or reduce the intracellular colonization and survival methods employed by this important opportunistic pathogen.